1. CATT (Comparison of Age-related Macular Degeneration Treatments Trials)1
Description A prospective, multicenter, single-blind, noninferiority randomized clinical trial. 1208 patients with neovascular AMD were enrolled from February 2008 and randomly assigned to receive intravitreal injections of ranibizumab (0.5 mg/0.05 ml) or bevacizumab (1.25 mg/0.05 ml) on either a monthly schedule or as needed with monthly evaluation. Patients aged ≥ 50 years with active, subfoveal CNV, fibrosis < 50% of total lesion area, visual acuity 20/25-20/320 and at least 1 drusen (>63μ) in either eye or late AMD in fellow eye were eligible. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart.
- At one year, all four groups had similar improvements in visual acuity.
- Groups had similar rates of adverse events, though patients receiving bevacizumab had more occurrences of ≥1 serious adverse event than those in the ranibizumab group.
- The annual cost of ranibizumab was more than 30x that of bevacizumab.
- Results from the two-year follow-up were similar, though the monthly administration groups outperformed the as-needed groups for gain in visual acuity.
2. EVEREST2-4 and PLANET study5
The EVEREST study was a multicenter, double-masked, primarily ICGA-guided trial. 61 Asian patients were randomized to verteporfin PDT (standard fluence), ranibizumab 0.5 mg, or the combination. Patients were administered with verteporfin PDT/placebo and initiated with three consecutive monthly RBZ/sham injections starting Day 1, and re-treated (Months 3-5) as per predefined criteria. The primary endpoint was the proportion of patients with ICGA-assessed complete regression of polyps at Month 6. Secondary endpoints included mean change in BCVA at Month 6 and safety.
Results Verteporfin PDT combined with ranibizumab 0.5 mg or alone was superior to ranibizumab monotherapy in achieving complete regression of polyps. All treatments were well tolerated over 6 months.
EVEREST II trial was conducted to compare the long-term effect of combination therapy vs ranibizumab monotherapy in symptomatic macular PCV over 24 months (2017).
- It was a multicenter, randomized, double-masked study where 322 patients with symptomatic macular PCV were randomized to combination therapy or ranibizumab, 0.5 mg, and sham PDT. All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. vPDT/sham PDT was done on day 1. The repeat vPDT/sham PDT was done on pro re nata regimen based on the presence of active polypoidal lesions but not before 3 months.
- 24-month data findings reported in july 2020 confirmed that combination therapy achieved superior BCVA gain, increased odds of complete polypoidal lesion regression, and fewer treatment episodes compared with ranibizumab monotherapy.
The PLANET study was a multicenter, double-masked, sham-controlled phase 3b/4 randomized clinical trial that was conducted from May 2014 to August 2016. 318 patients with symptomatic macular PCV were randomized to intravitreal Aflibercept (IVA) monotherapy or combined with vPDT. In both the groups patient not meeting rescue criteria were given 8 weekly IVA. Eyes with the suboptimal response (meeting rescue criteria) were to receive IVA 4 weekly plus sham vPDT (in IVA monotherapy group) or IVA 4 weekly plus rescue PDT (in the combined group). The primary objective of the study was to evaluate the efficacy and safety of IVA monotherapy and the noninferiority of IVA monotherapy to IVA/vPDT for mean change in BCVA from baseline to 52 weeks. Secondary objectives were to estimate the proportion of patients who required active PDT and whether active PDT was beneficial in eyes with suboptimal response to IVA monotherapy.
- IVA monotherapy was noninferior to IVA/vPDT in terms of BCVA.
- Proportions of patients with complete polyp regression or without active polyps were similar.
- In year 2, the mean number of injections was 4.6 in both arms.
- As < 15% met the criteria of suboptimal response to receive PDT, the potential benefit of adding PDT cannot be determined.
3. AREDS (Age-Related Eye Disease Study) 1 and 26-8
Description - The AREDS included two long term, multicentre, prospective, double masked clinical trials (one for AMD and one for cataract) with 4,757 participants, ages 55-80 years, enrolled in 11 clinics from 1992-98 and followed for a minimum of five years. The participants were categorized as no AMD, early AMD, intermediate AMD and advanced AMD and randomly selected to receive daily oral tablets for one of four treatments: 1) zinc alone; 2) antioxidants alone; 3) a combination of antioxidants and zinc; or 4) a placebo. The specific daily amounts of antioxidants and zinc used by the AREDS researchers were 500 mg of vitamin C; 400 international units of vitamin E; 15 mg of beta-carotene; 80 mg of zinc as zinc oxide; and 2 mg of copper as cupric oxide.
- Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.
- Use of a high-dose formulation of vitamin C, vitamin E, and beta carotene in a relatively well-nourished older adult cohort had no apparent effect on the 7-year risk of development or progression of age-related lens opacities or visual acuity loss.
The AREDS 2 was a multicenter, randomized, double-masked, placebo-controlled phase 3 study conducted in 2006-2012 to determine whether adding lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), or both to the AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta carotene, lowering zinc doses, or both in the AREDS formulation. It enrolled 4203 participants aged 50 to 85 years at risk for progression to advanced AMD with bilateral large drusen or large drusen in 1 eye and advanced AMD in the fellow eye. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD. However, because of potential increased incidence of lung cancer in former smokers, lutein + zeaxanthin could be an appropriate carotenoid substitute in the AREDS formulation.
4. ETDRS (Early Treatment Diabetic Retinopathy Study)9-11
Description A multicentre, randomized clinical trial designed to evaluate argon laser photocoagulation and aspirin treatment in the management of patients with NPDR or early PDR. 3711 patients were recruited from 1979-85 and followed for a minimum of 4 years. ETDRS defined the terms macular edema, CSME (clinically significant macular edema), mild, moderate, and severe NPDR, and early PDR (without the high-risk characteristics as described by DRS, the Diabetic Retinopathy Study).
Study measures and results
- To assess the benefits of early scatter laser photocoagulation in terms of severe visual loss and vitrectomy rate - Scatter treatment is not indicated for eyes with mild to moderate NPDR, provided that careful follow-up could be maintained. As the retinopathy progresses to the severe NPDR or early PDR, scatter treatment should be considered, especially for patients with Type 2 diabetes and it should be performed without delay for all eyes with high-risk PDR.
- To assess the effect of focal photocoagulation on macular edema in terms of moderate visual loss – Focal photocoagulation is recommended for eyes with CSME.
- To assess the role of aspirin - aspirin has no clinically important beneficial effect on the progression of retinopathy.
Recent trials in eyes with DME include READ-2 study (Ranibizumab vs laser or combination of both), RIDE and RISE, RESOLVE (Ranibizumab in DME), RESTORE (Ranibizumab or combination with laser vs laser alone), DA VINCI and VISTA (VEGF trap Eye in DME) and MEAD study (Dexamethasone implant in DME).
5. DRCR.net (Diabetic Retinopathy Clinical Research Network)
The DRCR.net was formed in September 2002 with principal emphasis on clinical trials on diabetic retinopathy (DR), diabetic macular edema (DME), and associated conditions.
Protocol S: Prompt Panretinal Photocoagulation (PRP) vs Intravitreal Ranibizumab (IVR) with deferred PRP for PDR Study12,13
Description – A randomized control trial on 394 eyes with PDR and visual acuity of 20/320 or better to determine if visual acuity outcomes at 2 years in eyes that receive anti-VEGF therapy with deferred PRP are non-inferior to those in eyes that receive standard prompt PRP therapy. 203 eyes received one to three sessions of PRP and 191 eyes received IVR (0.5 mg) at baseline followed by every 4 weeks for 6 months unless resolution was achieved after 4 injections. After 6 months, injections could be deferred if neovascularization was stable over 3 consecutive visits.
- At 2 years, there was no difference in terms of the final level of neovascularization. Mean change in VA from baseline was better in IVR group. PRP group had worse mean peripheral visual field sensitivity loss.
- At 5 years, the mean change in visual acuity was similar in both groups. IVR group had lower rates of developing vision-impairing DME and less visual field loss. Mean number of injections required was 19.2 in IVR group and 5.4 in PRP group.
Protocol T: A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema14
Description660 adults with center involving DME and Baseline visual acuity 20/32 to 20/320 were randomized to receive IVA (2 mg), IVB (1.25 mg) or IVR (0.3 mg). For the first 24 weeks, the study drugs were injected at baseline and then every 4 weeks unless visual acuity was 20/20 or better and a CMT below the eligibility threshold. Primary outcome measure was mean change in vision at 1 year.
- All drugs were found to be effective and safe in central DME. The trend of visual improvement was driven by baseline vision, and IVA was better than other drugs at worse levels of baseline vision (20/50 or worse). In eyes with mild vision loss, the efficacy was similar.
- The significant improvements in vision and reductions in macular edema on OCT at one year were sustained through two years with fewer injections and lasers than in the first year.
- The percentage of eyes gaining three lines of vision favored aflibercept at one year, but by year two there was no difference seen in the rates of three-line gainers
6. BVOS (Branch Vein Occlusion Study) 15,16
Description – a multi-center, prospective, randomized, controlled clinical trial on 500 patients (1984).
Study measures and results
- Whether scatter argon laser photocoagulation can prevent the development of neovascularization and vitreous hemorrhage - The study group recommended laser photocoagulation for patients with BRVO who have developed neovascularization and who meet the eligibility criteria.
- Whether macular argon laser photocoagulation can improve visual acuity in eyes with macular edema reducing vision to 20/40 or worse - The study group recommended laser photocoagulation for patients with macular edema associated with BRVO who meet the eligibility criteria.
- It was observed in the natural history of BRVO that 40% of the patients with > 5 DD of retinal capillary non-perfusion were at risk of developing retinal neovascularisation whereas 60% of these patients will experience vitreous hemorrhage.
Recent trials in eyes with BRVO include BRAVO trial (Ranibizumab for macular edema due to BRVO)
7. CVOS (Central Vein Occlusion Study) 17,18
Description a multi-centre, prospective, randomized, controlled clinical trial including 728 eyes of 725 patients seen in nine clinics with signs of CRVO (1988).
Study measures and results
- Whether early PRP can prevent NVI in ischemic CRVO - Eyes with less than 30 disc diameters of nonperfusion and no other risk factor were at low risk, whereas eyes with 75 disc diameters or more (ie, eyes that show virtually no intact capillaries in the posterior pole) are at the highest risk for development of 2 clock hours of NVI/NVA. Prophylactic PRP does not totally prevent NVI/NVA and prompt regression of NVI/NVA in response to PRP is more likely to occur in eyes that have not been treated previously.
- Whether grid pattern photocoagulation will reduce loss of central visual acuity due to macular edema secondary to CRVO - Macular grid laser photocoagulation had no effect on visual acuity despite reduced angiographic evidence of macular edema.
- Natural history of eyes with CRVO that have little or no evidence of ischemia (less than 10 disc areas of nonperfusion) was also studied.
Recent trials in eyes with CRVO include CRUISE (Ranibizumab for macular edema due to CRVO), COPERNICUS and GALILEO (intravitreal VEGF trap-eye for macular edema due to CRVO). In addition, The SCORE study evaluated Intravitreal triamcinolone acetonide for macular edema of CRVO and BRVO and the GENEVA study evaluated intravitreal Dexamethasone implant for macular edema due to BRVO or CRVO.
8. EVS (endophthalmitis vitrectomy study)19
Description multicenter, randomized clinical trial conducted from 1990 to 1995 in which 420 patients with clinical evidence of endophthalmitis within 6 weeks after cataract surgery or secondary intraocular lens implantation were randomized to one of the following two groups:
- Eyes received either initial pars plana vitrectomy (VIT) with intravitreal antibiotics (Vancomycin 1mg and Amikacin 0.4mg), followed by re-tap and reinjection at 36-60 hours for eyes that did poorly as defined in the study or
- Initial anterior chamber and vitreous tap/biopsy (TAP) with injection of intravitreal antibiotics (Vancomycin 1mg and Amikacin 0.4mg), followed by vitrectomy and reinjection at 36-60 hours in eyes doing poorly.
In addition, all eyes were randomized to either treatment or no treatment with intravenous antibiotics (Ceftazidime and Amikacin). Study end points were visual acuity and cclarity of ocular media assessed both clinically and photographically.
- In patients whose initial visual acuity was hand motions or better, there was no difference in visual outcome whether or not an immediate vitrectomy was performed. In patients with initial light perception-only vision, vitrectomy produced a 50% decrease in the frequency of severe visual loss.
- There was no difference in final visual acuity or media clarity with or without the use of systemic antibiotics.
- Microbiological results - undiluted vitreous produced a higher percentage of confirmed positive cultures. Eleven features of the initial clinical presentation were associated with significant differences in the microbiologic spectrum. Visual prognosis was strongly associated with the type of infecting organism and gram stain positivity.
9. Silicone oil study20,21
Description a randomized, multicenter surgical trial to compare the postoperative tamponade effectiveness of intraocular silicone oil with that of an intraocular long-acting gas (initially sulfur hexafluoride [SF6], later perfluoropropane [C3F8]) for the management of RD complicated by PVR, using vitrectomy and associated techniques (1985-91). A total of 151 eyes were randomized to receive either SF6 gas or silicone oil while 404 eyes were randomized to receive either C3F8 gas or silicone oil. Eligibility criteria included PVR of Grade C-3 or greater according to the Retina Society Classification and visual acuity of light perception or better. Endpoints of the study were visual acuity of 5/200 or greater and macular reattachment for 6 months following the final surgical procedure
- No significant differences in the rates of complete retinal attachment, visual acuity greater than 5/200 or glaucoma were found between treatment groups. The Silicone Study was the first study to document that the postoperative incidence rates of corneal abnormalities are equivalent between oil and gas. In contrast, gas-treated eyes had more hypotony.
- The occurrence of macular pucker following successful surgery for RD complicated by severe PVR was not influenced by the choice of intraocular tamponade.
- The identification of the anteroposterior extent of the PVR was prognostic of visual acuity and hypotony at 24 months. (The silicone oil study classification of PVR).
- Eyes with anterior PVR and clinically significant posterior PVR changes had a better visual prognosis if silicone oil rather than C3F8 gas was used.
10. ETROP (Early Treatment for Retinopathy of Prematurity Study)22
The CRYO-ROP study included premature infants less than 1,251 grams at birth and had a threshold level of ROP (defined as stage 3+ of the International Classification of Retinopathy of Prematurity occupying five or more contiguous or eight cumulative 30 degree sectors [clock hours] of stage 3 ROP in zone I or II in the presence of plus disease). It showed that cryotherapy reduces the risk of unfavorable retinal (by approximately one-half) and functional outcome from threshold ROP. The ETROP study tested the hypothesis of whether earlier treatment could result in an overall better visual outcome.
Description – A total of 317 infants with birth weights less than 1251 g and birth dates between 2000 and 2002 were enrolled at 26 participating centres. Earlier treatment was defined as retinal ablation administered to the avascular retina when an eye reached high risk prethreshold ROP which included any Zone I ROP; or Zone II stage 2 with plus disease, or stage 3; or Zone II with less than 5 contiguous or 8 cumulative clock hours of stage 3 ROP with plus disease. The functional outcome at 9 months corrected age was evaluated by assessment of monocular grating acuity (Primary outcome). The structural outcome was documented with a dilated fundus examination at 6 months and 9 months corrected age (Secondary outcome).
- Early treatment for Type 1 high-risk prethreshold eyes improved visual acuity outcomes at 6 years of age. Early treatment for Type 2 high-risk prethreshold eyes did not.
- A clinical algorithm (Type I or Type II ROP) was developed to identify for early treatment eyes with prethreshold ROP that are at highest risk for retinal detachment and blindness, while minimizing treatment of prethreshold eyes likely to show spontaneous regression of ROP.
The BEAT-ROP study evaluated the efficacy of intravitreal bevacizumab in ROP and compared it with conventional laser in infants ≤1500 grams at birth and ≤30 weeks gestation who develop Stage 3+ ROP in zone I or posterior zone II. Intravitreal bevacizumab monotherapy, compared with conventional laser therapy showed a benefit for zone I but not zone II diseases.
- 1. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119:1388-1398.
- Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. 2012;32:1453-1464.
- Koh A, Lai TY, Takahashi K, et al. Efficacy and safety of ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: a randomized clinical trial. JAMA ophthalmology. 2017;135:1206-1213.
- Lim TH, Lai TYY, Takahashi K, et al. Comparison of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: The EVEREST II Randomized Clinical Trial [published online ahead of print, 2020 Jul 16]. JAMA Ophthalmol. 2020;e202443.
- Wong TY, Ogura Y, Lee WK, et al, PLANET Investigators. Efficacy and safety of intravitreal Aflibercept for polypoidal choroidal vasculopathy: two-year results of the Aflibercept in polypoidal choroidal vasculopathy study. American journal of ophthalmology. 2019;204:80-89.
- Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 2001; 119:1417-1436.
- Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol 2001;119:1439-1452.
- Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: The Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial [published correction appears in JAMA. 2013 Jul 10;310(2):208]. JAMA. 2013;309:2005–2015.
- Early Treatment of Diabetic Retinopathy Study: Photocoagulation for diabetic macular edema. ETDRS report number 1. Arch Ophthalmol 1985; 103: 1796-806.
- Early Treatment of Diabetic Retinopathy Study: Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology. 1991; 98: 766-785.
- Early Treatment Diabetic Retinopathy Study Research Group: Effects of aspirin treatment on diabetic retinopathy. ETDRS Report Number 8. Ophthalmology 1991; 98: 757-765.
- Diabetic Retinopathy Clinical Research Network. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Trial. JAMA. 2015;314:2137-2146.
- Gross JG, Glassman AR, Liu D, et al. Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical trial. JAMA ophthalmology. 2018;136:1138-1148. 28.
- Diabetic Retinopathy Clinical Research Network, Wells JA, Glassman AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-1203.
- Branch Vein Occlusion Study Group: Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. Arch Ophthalmol 1986; 104:34-41.
- Branch Vein Occlusion Study Group: Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98:271-282.
- The Central Vein Occlusion Study Group: A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion. The CVOS Group N Report. Ophthalmol 1995;102:1434-1444.
- The Central Vein Occlusion Study Group: Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The CVOS Group M Report. Ophthalmol 1995;102:1425-1433.
- Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol 1995;113:1479-1496.
- Lean J, Azen SP, Lopez PF, et al. The prognostic utility of the Silicone Study Classification System. Silicone Study Report 9. Silicone Study Group. Arch Ophthalmol 1996;114:286-292.
- Abrams GW, Azen SP, McCuen BW 2nd, et al. Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up. Silicone Study report 11. Arch Ophthalmol 1997;115:335-344.
- Early Treatment for Retinopathy of Prematurity Cooperative Group: Final visual acuity results in the early treatment for retinopathy of prematurity study. Arch Ophthalmol 2010; 128: 663-671.